Inverted order: The direction of your DNA may be as important as which
parent it came from

Date:
January 4, 2022
Source:
University of Tsukuba
Summary:
Researchers generated mice with a specific DNA sequence inverted
to determine if orientation affects expression of a gene called H19.

Expression can also be impacted if the surrounding DNA is altered
by a process called methylation. Interestingly, methylation was
only relevant when the inverted sequence was inherited from the
father. When inherited from the mother, the inversion had the
opposite effect on H19 expression, suggesting a more complex
mechanism is at play.



FULL STORY ========================================================================== Mammalian offspring inherit two versions, or alleles, of each gene with
one allele from each biological parent. However, gene expression is
tightly regulated and certain genes undergo the phenomenon of "genomic imprinting," which is where only the allele received by the male or
the female parent is expressed. Imprinted genes play diverse roles in development and disruption of their mono-allelic expression can cause
diseases, thus understanding the mechanisms behind their regulation
is critical. In a recent article published in Communications Biology,
a team led by researchers at the University of Tsukuba examined genomic imprinting of a specific genetic locus in mice. Their experiments helped
reveal the molecular details of how this mechanism governs expression
levels of these genes.


==========================================================================
The team focused on the H19gene locus, which was previously shown to
be controlled by the H19 imprinted control region (ICR) via genomic
imprinting.

The paternal H19 ICR is modified via DNA methylation while the maternal
H19ICR allele isn't methylated. Methylation of the H19ICR is in part responsible for repressing the expression of H19.However, H19 itself
can also be methylated, and the effects of this had yet to be clarified.

"While the general imprinting mechanism for the mouse H19 locus is well established, it is less clear how expression of H19 is affected by its own methylation status," explains Assistant Professor Hitomi Matsuzaki, lead
author of the study. "Our previous finding suggested that the methylation
state of the H19ICR is transferred directionally downstream to H19in the fertilized embryo post-implantationwhich makes it difficult to study the
two in isolation." Then, the team hypothesized that by inverting the
H19ICR, thus reversing its direction, they could reduce H19methylation
and they created mutant mice to test this. Interestingly, with paternally inherited inverted ICR, H19had decreased levels of methylation and as a
result was derepressed. However, when the same experiments were conducted
for the maternally inherited inverted ICR, H19expression levels were lower compared with the un-inverted ICR allele, despite having low methylation.

"Our findings involving the maternally inherited allele were quite
unexpected, especially given the paternal data," describes Assistant
Professor Matsuzaki.

"We did observe slightly more ICR methylation in the inverted allele
compared with the wild type one." Further work did not provide evidence
that ICR methylation status was responsible for the differential
H19expression in the maternally inherited alleles. Collectively, these
data suggest that, for maternal inheritance, H19 expression is in fact
affected by the ICR orientation, but it is independent of DNA methylation.

Overall, Assistant Professor Matsuzaki and colleagues provided compelling insights into the complex nature of genomic imprinting in mice. The
methylation status and direction of certain DNA sequences can affect
genes found at the locus in different manners, and the effects also vary
based on which parent the allele was inherited from. These results shed
new light on the current knowledge and raise intriguing questions to be addressed by further studies.

This work was supported in parts by JSPS KAKENHI grants (grant numbers JP20K06481 to H.M., JP19H03134 to K.T., and JP20K21360 to K.T.), MEXT
KAKENHI grants (grant number JP20H05379 to H.M.), and a research grant
from the Takeda Science Foundation to K.T.

========================================================================== Story Source: Materials provided by University_of_Tsukuba. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Hitomi Matsuzaki, Yu Miyajima, Akiyoshi Fukamizu, Keiji Tanimoto.

Orientation of mouse H19 ICR affects imprinted H19 gene expression
through promoter methylation-dependent and -independent mechanisms.

Communications Biology, 2021; 4 (1) DOI: 10.1038/s42003-021-02939-9 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220104095557.htm
--- up 4 weeks, 3 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)